1. Field of the Invention
This application relates to methods for prophylactic and therapeutic treatment of balance impairments. More particularly, the application relates to prevention or therapy of ototoxin-induced balance impairments by administration of neurotrophins.
2. Introduction
Balance impairments are serious handicaps which affect millions of people. Balance impairments can be attributed to a wide variety of causes, including infections, mechanical injury, loud sounds, aging, and chemical-induced ototoxicity that damage neurons and/or hair cells of the peripheral vestibular systems. Vestibular ganglion neurons ("VGN"), which are primary afferent sensory neurons responsible for balance, deliver signals from the utricle, saccule and ampullae of the inner ear to the brain through the eighth nerve connecting primary auditory neurons in the spiral ganglia to the brain stem. Damage to the peripheral auditory system is responsible for a majority of balance deficits (Dublin, 1976; Lim, 1986) with destruction of vestibular ganglia neurons as a major cause of balance impairments.
During embryogenesis, the vestibular ganglion, spiral ganglion, and the otic vesicle are derived from the same neurogenic ectoderm, the otic placode. The vestibular ganglion neurons send peripheral neuronal projections to hair cells of the inner ear and extend central projections to the brainstem nuclei. This system is sensitive to ototoxins that include therapeutic drugs, antineoplastic agents, contaminants in foods or medicines, and environmental and industrial pollutants. Ototoxic drugs include the widely used chemotherapeutic agent cisplatin and its analogs (Fleischman et al., 1975; Stadnicki et al., 1975; Nakai et al., 1982; Berggren et al., 1990), commonly used aminoglycoside antibiotics, e.g. gentamicin, for the treatment of infections caused by Gram-negative bacteria, (Sera et al., 1987; Hinojosa and Lerner, 1987; Bareggi et al., 1990), quinine and its analogs, salicylate and its analogs, and loop-diuretics.
The toxic effects of these drugs on vestibular ganglion neurons are often the limiting factor for their therapeutic usefulness. For example, antibacterial aminoglycosides such as gentamicins, streptomycins, kanamycins, tobramycins, and the like are known to have serious toxicity, particularly ototoxicity and nephrotoxicity, which reduce the usefulness of such antimicrobial agents (see Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed., A. Goodman and Gilman et al., eds; Macmillan Publishing Co., Inc., New York, pp. 1169-71 (1980)). Aminoglycoside antibiotics are generally utilized as broad spectrum antimicrobials effective against, for example, gram-positive, gram-negative and acid-fast bacteria. Susceptible microorganisms include Escherichia spp., Haemohilus spp., Listeria spp., Pseudomonas spp., Nocardia spp., Yersinia spp., Klebsiella spp., Enterobacter spp., Salmonella spp., Staphyloccocus spp., Streptococcus spp., Mycobacteria spp., Shigella spp., and Serratia spp. Nonetheless, the aminoglycosides are used primarily to treat infections caused by gram-negative bacteria and, for instance, in combination with penicillins for the synergistic effects. As implied by the generic name for the family, all the aminoglycoside antibiotics contain aminosugars in glycosidic linkage. Ototoxicity is a dose-limiting side-effect of antibiotic administration. For example, nearly 75% of patients given 2 grams of streptomycin daily for 60 to 120 days displayed some vestibular impairment, whereas at 1 gram per day, the incidence decreased to 25% (U.S. Pat. No. 5,059,591). Ototoxicity is also a serious dose-limiting side-effect for cisplatin, a platinum coordination complex, that has proven effective on a variety of human cancers including testicular, ovarian, bladder, and head and neck cancer. Cisplatin damages vestibular systems (Fleischman et al., 1975; Stadnicki et al., 1975; Nakai et al., 1982; Carenza et al., 1986; Sera et al., 1987; Hinojosa and Lerner, 1987; Bareggi et al., 1990).
Accordingly, there exists a need for means to prevent, reduce or treat the incidence and/or severity of ototoxin-induced balance impairment related to vestibular neurons, particularly that arising as an unwanted side-effect of ototoxic therapeutic drugs, which include cisplatin and its analogs and aminoglycoside antibiotics. In addition, there exits a need for methods that allow higher and thus more effective dosing with these ototoxicity-inducing balance-impairing therapeutic drugs by concomitantly preventing or reducing the ototoxic effects of these drugs. What is needed is a method that provides a safe, effective, and prolonged means for prophylactic or curative treatment of ototoxin-induced balance impairment. In addition there is needed a rapid, reliable, and facile system for testing the effects and mechanisms of ototoxins on balance in animals, including humans, and for testing the efficacy of therapeutics to prevent, reduce or treat these impairments. The present invention provides such methods and systems to achieve these goals and others as well.